Metazoan tissues are complex assemblies of cell populations that often differ in their ability to proliferate. How cells communicate their growth status during tissue expansion, be it developmental or homeostatic, is largely unknown. This fundamental question is important to many aspects of medicine and health, including organ regeneration and transplantation; stem cell biology, and cancer. In previous work we obtained results suggesting that cells measure their growth and metabolic potential through local cell-cell signaling. Additional findings indicated that cellular metabolism is altered in each cell population during the signaling exchange. Third, results were obtained that showed that p53 plays a key role in the cellular metabolic changes. We propose experiments to build upon these results in Drosophila, to take advantage of its powerful genetic and molecular tools. We will use genomic profiling, genetic analysis of mutants, somatic cloned techniques, and in vitro and in vivo biochemical and molecular analysis to achieve three specific aims: To continue to uncover and functionally validate genes and signaling pathways that are important during cell competition, to identify the active factors in competitive CM that lead to death of loser cells and proliferation of winner cells, and to determine the role of p53 and its targets in sensing and regulating metabolic changes during competition. These studies will reveal mechanisms underlying interactions between cells in growing epithelia that may be valuable for improving the health and care of humans. In addition, they will expand our understanding of fundamental aspects of cell-cell communication during growth. PUBLIC HEALTH RELEVANCE: Our previous work using Drosophila as a model system has demonstrated that competition can be induced between neighboring cells that grow at different rates within developing tissues. During cell competition, metabolic differences are sensed between cells that lead to cellular and tissue-wide decisions about survival and growth. The outcome of competition directly influences tissue growth and fitness, yet we know little about how it is physiologically regulated. Our work has demonstrated that a key role is played by the conserved transcription factor, Myc, which critically influences cellular biosynthesis and metabolism. Cell competition has remarkable similarities to the early stages of cancer, thus we anticipate that this work will aid in the identification of markers distinguishing early cancer cells from their wildtype neighbors. Furthermore, mechanisms that ensure tissue fitness are critical for regeneration and tissue transplantation, animal aging and longevity, and also to our understanding of the basic biological properties of cell communication during growth.